Optically Active Dioxatetraazamacrocycles: Chemoenzymatic Syntheses and Applications in Chiral Anion Recognition Ignacio Alfonso, Francisca Rebolledo, and Vicente Gotor* [a] Dedicated to Professor JoseÂElguero on the occasion of his 65th birthday Abstract: Two new C 2 and D 2 symmet- rical dioxatetraaza 18-membered mac- rocycles [(R,R)-1 and (S,S,S,S)-2] are efficiently synthesized in enantiomeri- cally pure forms by a chemoenzymatic method starting from ()-trans-cyclo- hexane-1,2-diamine. The protonation constants and the binding constants with different chiral dicarboxylates are deter- mined in aqueous solution by means of pH-metric titrations. The triprotonated form of (S,S,S,S)-2 shows moderate enantioselectivity with malate and tar- trate anions (DDG  0.62 and 0.66 kcal mol 1 , respectively), being the strongest binding observed in both cases with the l enantiomer. Good enantiomeric dis- crimination is obtained with tetrapro- tonated (R,R)-1 and N-acetyl aspartate, the complex with the d-enantiomer being 0.92 kcalmol 1 more stable than its diastereomeric counterpart. Despite the lack of enantioselectivity of tri- and tetraprotonated (R,R)-1 for the tartrate anion, a very good diastereopreference for meso-tartrate is found. All these experimental results allow us to propose a model for the host±guest structure based on coulombic interactions and hydrogen bonds. Keywords: chiral anion recognition ´ enantiomeric resolution ´ host± guest chemistry ´ macrocycles ´ molecular recognition Introduction Oxaazamacrocycles are attractive molecules with a variety of applications in the fields of supramolecular chemistry and catalysis. [1] The presence of two kinds of heteroatoms (nitro- gen and oxygen) in the macrocyclic ring confer hybrid properties, between those of azacrowns and crown ethers, on these structures. [2] Thus, depending on structural factors like size of the ring or number and disposition of the heteroatoms, these systems are able to form kinetically and thermodynamically stable complexes with different metals. [3] Furthermore, when protonated, they are excellent anion binders. [4] For instance, some of these compounds are receptors for biologically important anions like nucleotides and nucleic acids. The complexation affects the reactivity of the anion, leading to interesting applications in supramolec- ular catalysis. Therefore, 24- to 36-membered-ring oxaaza- macrocycles have been extensively studied for their ATPase, [5] phosphorylase [6] , and enolase [7] activities in comparison with the normal enzymatic catalysis. However, the design and synthesis of selective receptors for optically active polyanions still constitutes a difficult task facing chemists. Although cyclodextrins have proved to be excellent ligands for the recognition of helicity, [8] only low selectivities have been obtained with compounds bearing chiral centers. [9] Recently, sapphyrin-based receptors [10] have been successfully used for the recognition and transport of aspartate and glutamate derivatives; these are the first receptors capable of the selective recognition of dianionic dicarboxylates with chiral centers. Taking into account the interest and scarcity of suitable optically active macrocycles that act as selective receptors of chiral anions, [11] in this work we aimed at the synthesis of optically active oxaazamacrocycles 1 and 2, with C 2 and D 2 symmetry, respectively, by a chemoenzymatic method. In addition, we studied their protonation and their chiral anion recognition properties in aqueous solution, since this is the natural environment of biologically important anions. Results and Discussion Design and synthesis : Structural complementarity in molec- ular recognition is crucial for the success of a given receptor. [12] Coulombic attractions and hydrogen-bond for- [a] Prof. Dr. V. Gotor, Dr. I. Alfonso, Dr. F. Rebolledo Departamento de Química Orga Ânica e Inorga Ânica Universidad de Oviedo 33071 Oviedo (Spain) Fax: ( 34)98-510-3448 E-mail: vgs@sauron.quimica.uniovi.es Supporting information for this article is available on the WWW under http://www.wiley-vch.de/home/chemistry or from the author. FULL PAPER Chem. Eur. J. 2000, 6, No. 18  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 0947-6539/00/0618-3331 $ 17.50+.50/0 3331